New insight into the progression of tuberculosis infection

05 September 2016

An international research team led by UK scientists has found
clear evidence of a separate stage in tuberculosis (TB) infection
where people have no symptoms but are more likely to go on and
develop the full disease. The findings, published
in Nature Medicine, suggest it may be possible to
identify which people are most at risk of developing TB and can be
treated in a more targeted way.

Professor Robert Wilkinson of the Francis Crick Institute and
Imperial College London led a team including scientists from the
University of Cape Town, South Africa, and the US National
Institute of Health. He says: "We have shown clear evidence for a
TB stage in-between latent infection and active disease. It could
lead to a way of predicting which infected individuals will develop
TB disease and transmit it on to others."

The results also offer hope in controlling the spread of
disease. Robert says: "People ill with TB can infect up to 10-15
other people through close contact and if we can identify people in
the transition stage before they transmit to other people, that's
potentially a game-changer in terms of TB eradication."

Conventionally, TB infection is classed into two stages:
'latent' and 'active'. People with latent infection test positive
for an immune response to the TB bacteria, Mycobacterium
tuberculosis, but do not have the symptoms of active disease.
Around 10% of people with latent TB infection progress to active
disease if left untreated. However, currently there is no accurate
way to predict which infected individuals will develop the
disease.

It is estimated that there are 2 billion people around the world
with latent TB infection. Active TB kills an estimated 1.5 million
people annually - with people with HIV being at greater risk.

The researchers screened 265 HIV-positive people for TB
infection in a township in Cape Town, South Africa where TB
incidence is high. Of those who tested positive for latent TB, 35
were recruited to the study and were followed up over a period of
six months.

The team used a combination of medical imaging techniques to
study the lungs of the 35 patients - positron emission tomography
(PET) and computed tomography (CT) scans - which highlighted
areas of lung abnormalities as 'hot spots'.

Ten out of the 35 participants with latent TB infection had lung
abnormalities consistent with a transitional or subclinical stage
of TB progression. The other 25 participants had no hot spots and
showed no signs of disease progression.

Over the course of the study, four of the 10 patients with lung
abnormalities developed fully-fledged TB symptoms and started full
treatment for TB. Two of these were found to have active TB
confirmed by a standard sputum culture that tests for the presence
of TB bacteriain the airways.

"We found evidence of differences in disease progression within
a group of people that currently would all be diagnosed and managed
as having the same latent TB infection, as none of them showed any
outward symptoms of TB," Robert explains. "Those that had evidence
of 'subclinical' disease on the PET/CT scans were at higher risk of
developing the disease."

Imaging was continued during the treatment period for the four
patients with active TB. This showed the lung abnormalities
gradually diminishing over time. Robert says: "These high-tech
images provide us with new ways to evaluate whether treatment has
cured an infection. Most importantly, it will show whether we need
to treat for the full recommended duration of six months, as most
patients find the standard six months regimen of two or three
different antibiotics very challenging."

Robert adds: "It would not be feasible to PET/CT scan everyone
with latent TB as the majority of these people are in poor regions
of sub-Saharan Africa and these particular scanners are expensive.
Instead, the study is most promising in enabling other markers of
this 'sub-clinical' stage of infection to be identified and be able
to better predict those who will develop TB symptoms."

The research was supported by Wellcome, the Bill and Melinda
Gates Foundation, the US National Institutes of Health, the
National Research Foundation of South Africa, the Francis Crick
Institute, the Medical Research Council of South Africa, and the
European Union.

An international research team led by UK scientists has
found clear evidence of a separate stage in tuberculosis (TB)
infection where people have no symptoms but are more likely to go
on and develop the full disease.

The findings, published in Nature
Medicine, suggest it may be possible to identify which
people are most at risk of developing TB and can be treated in a
more targeted way.

The Francis Crick Institute is a unique partnership between the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King's College London.

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